Peripheral afferent neuronal barrage from tissue injury produces central nervous system (CNS) hyperexcitability, which may contribute to increased postoperative pain. Blockade of afferent neuronal barrage has been reported to reduce pain following some, but not all, types of surgery. This study evaluated whether blockade of sensory input during and immediately after oral surgery with a long- acting local anesthetic reduces postoperative pain after the anesthetic effects have dissipated. Forty-eight patients underwent oral surgery with general anesthesia in a parallel-group, double-blind, placebo-controlled study. Subjects randomly received either 0.5 percent bupivacaine or saline intraoral injections; general anesthesia was induced with propofol, a non-opioid anesthetic; and two to four third molars were extracted. Subjects were assessed at 24 and 48 hours for postoperative pain and analgesic drug intake. Blood samples were collected at baseline, intraoperatively and at 1-hour intervals postoperatively to measure beta-endorphin as an index of CNS response to nociceptor input. Pain intensity was not significantly different between groups as measured by category scale and graphic rating scales for pain and unpleasantness (p<0.05). Additionally, subjects in the bupivacaine group self-administered fewer codeine tablets for unrelieved pain over 24 to 48 hours postoperatively (p<0.05). Plasma heta-endorphin levels increased significantly from baseline to the end of surgery in the saline group in comparison to the bupivacaine group (p<0.05), indicating effective blockade of nociceptor input into the CNS by local anesthetic. These data support previous animal studies demonstrating that blockade of peripheral nociceptive barrage during and immediately after a surgical procedure results in decreased postoperative pain. The results suggest that administration of a long-acting local anesthetic before oral surgery decreases hyperexcitability, resulting in less pain and analgesic intake.